Our efforts in the past 23 years to study the chemistry and biology of nucleic acids in an integrated and comprehensive manner will be continued. This program has two sections: (1) The physico-chemical properties and interactions of nucleic acids will be studied by NMR on 1H, 13C, 31P and 19F nuclei with the best spectrometer available. This project is made possible by the organic/biochemical synthesis of short helices, analogs, 13C or 19F labeled nucleic acid, etc., and by computer technology, with graphic facilities for improvement of NMR theory. A 10-nucleotide long helix of DNA has now been synthesized and is under active investigation by NMR and other spectroscopic methods. (2) The structure and function of nucleic acids having specific, exposed/accessible sequences will be probed by appropriate oligonucleotide analogs (alkyl phosphotriesters or phosphonates, up to a decamer long) inside the living cells. These compounds form specific duplexes with complementary sequences, penetrate living cells, and resist enzyme degradation. Sequences in tRNA, mRNA, rRNA and oncogenic viral RNA inside the living cells can be interacted with these analog probes, so that their functions can be analyzed, modified and controlled. Several specific non-ionic analogs were shown to have specific biological activities against bacteria but not mammalian cells.